Apoptosis is closely involved in morphogenesis and histogenesis in the development process of the organism, maintenance of homeostasis, biological defense, etc. and is cell death having an important role in maintaining individual lives. When the death process regulated by genes is congenitally or postnatally hindered, apoptosis is excessively induced or inhibited to cause functional disorders in various organs and thus illness (Saishin Igaku, 54, 825, 1999).
In recent years, it has been revealed that apoptosis is closely involved in onset or progress of various heart diseases (The New England Journal of Medicine, 341, 759, 1999). In a mammalian heart, it is considered that cardiomyocytes are finally differentiated cells and their proliferation activity is lost. Accordingly, when cardiomyocytes are lost due to apoptosis, the heart contraction should be maintained only by the surviving cardiomyocytes. It is thus considered that the loss of cardiomyocytes beyond the threshold necessary for maintaining the heart contraction would result in abnormal heart functions to cause diseases. In fact, apoptosis of cardiomyocytes is observed in various animal models with heart failure or in human patients with heart failure, indicating that disappearance or loss of cardiomyocytes due to apoptosis may contribute to the onset and progress of heart failure (The New England Journal of Medicine, 335, 1182, 1996). It is further recognized that in cardiomyocytes of human patients with heart failure, an apoptosis inhibitory factor Bcl-2 is expressed in excess, which is a possible compensation mechanism for heart failure (The New England Journal of Medicine, 336, 1131, 1997); that serum levels of soluble Fas (sFas, which has an apoptosis inhibitory activity), which lacks a membrane penetration domain in the Fas receptor known as an apoptosis inducing receptor, are increased significantly in proportion to severity in NYHA class (New York Heart Association Functional Class) but independently of fundamental diseases, and thus an increase in serum levels of sFas is considered to be a compensatory mechanism to inhibit promotion of apoptosis in heart failure (Journal of the American College of Cardiology, 29, 1214, 1997). It is also recognized that in the heart with congestive cardiomyopathy, deoxyribonuclease I (DNase I) considered as a indicator of apoptosis is increased 7-fold or more, as compared to healthy persons (Journal of Molecular & Cell Cardiology, 28, 95, 1996).
When considered at the level of internal organs, the functions of the heart muscle are lowered in human cardiac diseases and failure of myocardial contraction often endangers the maintenance of the life. Abnormalities including myocardial disorders, abnormal heart pumping, pressure load due to hypertension, etc., volume load due to acute nephritis, etc, and insufficient blood pumping caused by these abnormalities lead to the onset of heart failure. Against these abnormalities, the sympathetic nervous system, the endocrine system, and the like work together to serve as a compensatory mechanism, which results in cardiac hypertrophy accompanied by hypertrophy of cardiomyocytes. However, when these abnormalities occur alone or in combination persistently and chronically, the hypertrophied cardiomyocytes are not sufficiently supplied with blood, and thus the cardiomyocytes are lost due to apoptosis, etc. As a result, the compensatory mechanism fails to work, leading to a heart failure syndrome accompanied by myocardiopathies such as myocardial stunning, reduced cardiac output, circulatory disorders in internal organs, venostasis, fluid retention, etc.
At present, the heart failure syndrome is treated by using cardiotonic glycosides such as digoxin, etc., sympathetic agents such as dobutamine, etc., phosphodiesterase inhibitors such as amrinone, etc., vasodilators such as hydralazine, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, etc., and congestive cardiomyopathy is treated by β-blockers, etc.
On the other hand, 1,3-benzothiazinone compounds substituted with phenyl at the 2-position are reported in Chemical Abstracts, 119:122687, Chemical Abstracts, 119:16999, Chemical Abstracts, 117:200467, Chemical Abstracts, 116:214422, Chemical Abstracts, 116:21013, Chemical Abstracts, 112:215913, Tetrahedron, 44, 2985-2992, 1988, Chemical Abstracts, 105:144960, Chemical Abstracts, 103:37436, Chemische Berichte, 108, 2523-2530, 1975, Chemical Abstracts, 93:167097, Chemical Abstracts, 85:21262, Chemical Abstracts, 71:91408 and JPA No. 3-229241, but any relation to a macrophage migration inhibitory factor is not described therein.
Furthermore, 1,3-benzothiazinone compounds having a cardiomyocyte apoptosis inhibitory activity are disclosed in WO 02/18356, specifically 2-(2-pyridyl)-4H-1,3-benzothiazin-4-one, 2-(3-pyridyl)-4H-1,3-benzothiazin-4-one, 2-(4-pyridyl)-4H-1,3-benzothiazin-4-one, 2-(4-oxo-3,4-dihydro-2H-1,3-benzothiazin-2-ylidene) ethyl acetate and 2-[2-oxo-2-(1-piperidinyl)ethylidene]-2,3-dihydro-4H-1,3-benzothiazin-4-one.